Project Summary/Abstract Suicide is the second leading cause of death (behind accidents) among those ages 10-34 years in the US and is the cause of mortality most strongly linked to mental illness. Starting at approximately age 12 years, the rate of suicidal thoughts and behaviors (STBs) increases dramatically, especially among girls, who experience STBs at twice the rate for boys. These pronounced increases for adolescents and for girls have been well-documented for decades and are seen in virtually every country/culture around the world, yet, there is no firm understanding of why they exist. Moreover, very little is known about when risk is highest. The proposed research extends our team?s prior work, funded by two prior R01 awards, examining adolescent girls? stress responses as prospective predictors of STB trajectories, and a K99/R00 award revealing that changes in reproductive hormones across the menstrual cycle produce specific periods of high STB risk (particularly during the peri-menstrual phase) among adult women. Specifically, we hypothesize that girls will report higher occurrence and severity of STBs on days in the peri-menstrual phase than on days in other cycle phases (mid-follicular, ovulatory, mid-luteal), that these increases will be mediated by daily changes in negative affect and stress-reactivity during the peri- menstrual phase, and that girls with greater cyclical hormone sensitivity are at greater long-term risk of STBs, particularly during times when interpersonal stress is elevated. We propose to test these hypotheses in a sample of 200 clinically-referred girls ages 12-17 years who are at least one year post-menarche. The design begins with 70 days (two cycles) of daily surveys to assess negative affect and STBs. In addition, girls will complete two counterbalanced laboratory visits (at high risk peri-menstrual and low risk mid-follicular phases) during which we will evaluate their affective and physiological (autonomic, cortisol, genomic) responses to a standardized laboratory stressor. Next, girls will complete weekly surveys measuring cycle phase, interpersonal stress, negative affect, and STBs through one year of follow up. The intensive two-month baseline phase allows us to examine how the menstrual cycle shapes daily affective and physiological risk for STBs and lets us diagnose each girl?s degree of hormone sensitivity. These baseline individual differences in hormone sensitivity then can be examined as a predictor of STBs across the follow-up year of assessments, particularly during periods of elevated social stress. This powerful design will clarify whether cyclical changes in daily STBs (Aim 1) are mediated by affective and physiological STB risk factors, such as negative affect (Aim 2a; measured via daily surveys) and social stress reactivity (Aim 2b; measured via lab-based behavioral, physiological, and molecular biomarker assays), while also acknowledging critical moderation by both individual differences in hormone sensitivity (i.e., not all girls will have severe cyclical mood changes) and time-varying interpersonal stress (Aim 3). This innovative study will address several long-standing questions in the literature, including why girls are at increased risk, when girls may be most at risk, and which girls are at highest risk for future STBs.